(3) Brady, 0. L., Cosson, A. N.. Roper, A. J., J. Chem. SOC., 127, 2427 (1925). (4) Davey. W.. Gwilt, J. R., J. Chem. Soc., 204 (1950). (5) Davey, W., Gwilt, J. R., J. Chem. Soc., 3348 (1950). (6) Davey, W., Gwilt, J. R., J. Chem. Soc., 1384 (1955). (7) Lieberman, S. V., Connor, R., "Organic Synthesis", Coll. Vol. (I,Wiley, New York, N.Y.. 1943, p 441. ( 8 ) Nishimura, T.. ref 7, Coll. Vol. IV. 1963, p 713. (9) Scheibler, H.. Sotschech, F., Friese, H., Chem. Ber., 57, 1443 (1924). (10) Silverstein, R. M.. Bassler. G. C., Morrill, T. C.. "Spectrometric Identification
of Organic Compounds", Wiley, New York, N.Y. 1974, p 262. (11) Thiele, J., Winter, E., JustusLiebigs Ann Chem., 311, 356 (1900). (12) Tsang, S.M., Wood, E. H., Johnson, J. R.. ref 7, Coll. Voi. 3, 1955, p 641. (13) Wegscheider R., Spath, E., Monatsh. Chem., 30, 825, 840 (1909). (14) Van der Beek, P. A. A., Red. Trav. Chim. Pays-Bas, 47, 304 (1928). (15) Van Peski, A. J., Recl. Trav. Chim. Pays-Bas, 40, 117 (1922). Received for review August 9, 1976. Accepted October 21, 1976.
Synthesis of Potential Specific Inhibitors of Certain Amino Acid Decarboxylases Zafar H. Israili't and Edward E. Smissman* Department of Medicinal Chemistry, School of Pharmacy, University of Kansas, Lawrence, Kansas 66044
A number of potential specific inhibitors of amino acid decarboxylases were synthesized by subjecting amino acids and their derivatives to Dakin-West reaction conditions. In some cases the Dakin-West conditions were modified. Pyridine and imidazole were found to be suitable as bases in the Dakin-West reaction. The Dakin-West reaction (3) on a-amino acids yields 1substituted-1-N-acetamidopropanones. The acetamidopropanone obtained from histidine as well as the aminopropanone (obtained by the hydrolysis of the acetamidopropanone) have been shown to be specific inhibitors of histidine decarboxylase
(7-9). This report is a continuation of our attempts (6-8) to synthesize active-sitedirected reversible inhibitors of enzymes utilizing amino acids as substrates. Potential inhibitors of specific amino acid decarboxylases were synthesized by subjecting selected amino acids and their derivatives to Dakin-West reaction conditions. In some cases the Dakin-West reaction was modified to obtain the desired products (Tables 1-111) (Figure 1). L-Cysteine (I) underwent Dakin-West reaction to give 4acetylthio-3-acetamido-2-butanone (11) (Table I).Acid hydrolysis of II afforded 4-mercapto-3-amino-2-butanone hydrochloride (Ill). Treatment of compound II with trifluoroacetic anhydride yielded the oxazole IV (Table II) along with a small amount of the free mercaptooxazole V (4-mercaptomethyl-2,5-dimethyloxazole), identified by its NMR spectrum. L-Cysteine hydrochloride monohydrate was dehydrated to cysteine hydrochloride ( 7) which in turn was converted quantitatively to S-benzhydrylcysteine ( 4 ) (VI). Compound VI upon treatment with Ac20 and pyridine gave 4-diphenylmethylthio3-acetamido-2-butanone (VII). S-Triphenylmethylcysteine (VIII) was obtained from L-cysteine hydrochloride ( 73)and converted to 4-triphenyl-methylthio-3-acetamido-2-butanone(IX). m-Methionine (X) gave the normal Dakin-West product XI. The acetamido ketone XI was converted to the corresponding oxazole XII. The Dakin-West reaction on L-proline (XIII) or Kacetyl-Lproline (obtained in 95% yield from XIII, AclO, and pyridine) or Ktrifluoroacetyl-L-proline (XIV) was unsuccessful. Compound
+ Address correspondence to this author at the Department of Medicine, Clinical Pharmacology Program, Emory University, Atlanta, Georgia 30322. Deceased, July 14, 1974.
Compound
R,
R2
I1 Ill VI VI I Vlll IX XI XIX XXlll XXlV XXVl XXVlll XXlX
COCH, H.HCI
COCH, COCH, COOH COCH, COOH COCH, COCH, COCH, COOH
H COCH,
H COCH, COCH, COCH, COCF, COCF, COCF, COCH, COCH,
COI 2 0 COOC,H, COCH, COCH,
Table II
R,
Compound
IV V XXI I
~
CH,COS HS CH,SCH, CH,COOCO HOOC C6H5
xx XXI
xxv
R:_
_
CH1 CH3 CH, CH, CH, CF,
RZ Compound
R,
RI
R,
XIV
H [H =O
COCF, COCF, COCH,
COOH C O I >o COCH,
xv XVI I
Journal of Chemical and Engineering Data, Vol. 22, No. 3, 1977
357
_
Table 111 Starting compound
Product
Yield, %
Mp (solvent)= or bp (OC) (at mm pressure)
I
II
73
81-82 (benzene)
II II
111 IV
13 70
132-133.5 (i-PrOH) 7910.35 mm
VI
VI1
38
94-95 (CHC13-EtzO)
Vlll X XI
IX XI XI1
12 80 42
116-1 19 (CHCI3-EtzO) 13810.25 mm 6810.5 mm
Xlll
XIV
57
XVI
XVll
30
E
15
